Prenatal Expression Patterns of Genes Associated With Neuropsychiatric Disorders

OBJECTIVE Neurodevelopmental disorders presumably involve events that
occur during brain development. The authors hypothesized that
neuropsychiatric disorders considered to be developmental in etiology
are associated with susceptibility genes that are relatively upregulated
during fetal life (i.e., differentially expressed). METHOD The authors
investigated the presence of prenatal expression enrichment of
susceptibility genes systematically, as composite gene sets associated
with six neuropsychiatric disorders in the microarray-based "BrainCloud"
dorsolateral prefrontal cortex transcriptome. RESULTS Using a
fetal/postnatal log2-fold change threshold of 0.5, genes associated with
syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3),
intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum
disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal
transcript abundance, compared with the overall transcriptome. Genes
associated with schizophrenia by genome-wide association studies were
not preferentially fetally expressed (N=106 genes, p=0.46), nor were
genes associated with schizophrenia by exome sequencing (N=212 genes,
p=0.21), but specific genes within copy-number variant regions
associated with schizophrenia were relatively enriched in prenatal
transcript abundance, and genes associated with schizophrenia by
meta-analysis were functionally enriched for some neurodevelopmental
processes. In contrast, genes associated with neurodegenerative
disorders were significantly underexpressed during fetal life (N=46
genes, p=1.67×10-3). CONCLUSIONS The authors found evidence for relative
prenatal enrichment of putative susceptibility genes for syndromic
neurodevelopmental disorders, intellectual disability, and autism
spectrum disorder. Future transcriptome-level association studies should
evaluate regions other than the dorsolateral prefrontal cortex, at
other time points, and incorporate further RNA sequencing analyses.

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